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Biomedical subjects

M A Baird

Publications and source records attributed to M A Baird.

At least 19 recordsLinked to original sources
PubMed2003

Transfer of macrophage-derived mycobacterial antigens to dendritic cells can induce naïve T-cell activation.

Mycobacteria are capable of surviving and replicating in host macrophages, where they can release antigenic material into the environment. However, unlike dendritic cells (DCs), macrophages do not appear to be capable of activating naïve T cells. Therefore, this work investigated antigen transfer between macrophages and DCs. We generated culture supernatants from bacille Calmette-Guérin (BCG)-infected and uninfected macrophages and then determined whether DCs could present these extracellular mycobacterial antigens to T cells. Here, we show that DCs pulsed with antigens released from BCG-infected macrophages can stimulate primed T cells in vitro and initiate naïve T-cell responses in vivo. These results suggest that antigen transfer can occur between macrophages and DCs.

Animals↗
PubMed2000

Targeting early events in T cell activation to construct improved vaccines.

Live, attenuated vaccines currently offer the best protection against virulent pathogens. Recent advances in Immunology and Molecular Biology provide an opportunity to design vaccines that will be more effective and safer than existing ones. Immunologists are rapidly developing the capacity to identify and construct the minimal immunogenic units from pathogens. The molecular signals required to fully activate antigen presenting cells (APCs) and responder T cells are becoming apparent. Improved vaccine delivery systems are being designed which will mimic the actions of pathogens in vivo. These vaccines will incorporate protective epitopes fused to immunoregulatory cytokines in chimeric proteins. They will be encapsulated in formulations which allow for the slow release of these chimeric proteins thereby inducing the memory T cells required for long-lived immunity. These vaccine formulations will target receptors present on the most active APCs. Here we discuss how these advances will allow us to rationally construct "virtual pathogens" which will provide improved protection against new and old microbial foes.

Adjuvants, Immunologic↗
PubMed1998

A long-lasting interferon-gamma response is induced to a single inoculation of antigen-pulsed dendritic cells.

Vaccines against infectious organisms must produce not only long-lasting immunity but also the appropriate immune response to clear the infection. Obligate intracellular parasites, such as mycobacteria, require a predominantly cell-mediated immune response rather than antibody. Presentation of antigen by dendritic cells (DC) has been associated with the development of strong cell-mediated responses generating the production of interferon-gamma (IFN-gamma). This cytokine has an essential role in the elimination of mycobacteria. Therefore, we investigated both the duration and the nature of the immune response after priming with DC pulsed with mycobacterial antigen and compared this with priming using a conventional adjuvant. We used two strains of mice: C57BL/6, which inherently produces a T-helper 1 (Th1)-type response to mycobacterial antigen, and BALB/c, which does not. DC-enriched cell suspensions, purified DC or cultured bone marrow cells resembling DC (BMAPC) were prepared, pulsed overnight with PPD and injected intravenously (i.v.) into naive mice. Six and 12 weeks later, splenic T lymphocytes from these mice were challenged in vitro with antigen and their proliferative response and cytokine production was determined. Significant antigen-specific proliferation was observed in all assays on rechallenge with antigen in vitro 6 and 12 weeks after the initial priming with DC. IFN-gamma was detected in both strains but was only antigen specific in the C57BL/6 strain. Purified protein derivative (PPD)-pulsed BMAPC generated similar responses 6 weeks after priming. Thus, long-term T-lymphocyte responses and the production of IFN-gamma can be generated using a single inoculation of PPD-pulsed DC.

Animals↗
PubMed1998

Blockade of B7-2, not B7-1, inhibits purified protein derivative-primed T-lymphocyte responses but fails to influence the proportion of Th1 versus Th2 subsets.

The ability to select for a cell-mediated response rather than antibody production following infection with intracellular mycobacteria, would be an advantage in preventing the occurrence of disease. Recent work suggests that the two members of the B7 family of costimulatory molecules, B7-1 and B7-2, may differentially influence the nature of primary immune responses but little is known of their role in this capacity in secondary responses. We have used an in vitro model to investigate whether blocking B7-1 and B7-2 affects changes in the cytokine profiles of Th lymphocytes previously primed to purified protein derivative (PPD) from Mycobacterium bovis. In C57BL/6 and BALB/c mice we found that the proliferative responses of a component of recently activated T lymphocytes, and those returning to the resting state, were inhibited by B7-2 blockade. B7-1 blockade had no distinguishable effect. However, in cultures containing anti-B7-2 antibody, the production of both interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), indicative of cell-mediated and antibody responses, respectively, were reduced. This suggests that intervention in a recall response to mycobacterial antigen by blocking B7-1 or B7-2 molecules, is unlikely to alter the nature of the immune response.

Animals↗
PubMed1997

Priming to mycobacterial antigen in vivo using antigen-pulsed antigen presenting cells generated in vitro is influenced by the dose and presence of IL-4 in APC cultures.

Antigen presenting cells (APC) similar to immature dendritic cells can be generated in vitro from bone marrow precursors. The authors have compared the yield, the phenotype and the function of murine bone marrow cells cultured for 7 or 11 days in either granulocyte macrophage colony stimulating factor alone (GM BMAPC) or in combination with interleukin-4 (GM/IL-4 BMAPC). The results showed that GM/IL-4 BMAPC expressed the highest levels of MHC Class 2 molecules, CD86/B7-2 and CD80/B7-1 co-stimulatory molecules and the lowest levels of F4/80 macrophage marker. However, when these APC were pulsed with BCG culture filtrate antigen or PPD they were not correspondingly more effective at stimulating activated T lymphocytes in vitro or priming naive T lymphocytes in vivo. Also, in contrast to GM BMAPC, high backgrounds recorded following injections of GM/IL-4 BMAPC without antigen were not consistently reduced by lowering the dose and irradiating the cells prior to administration. The authors conclude that the degree of maturity of BMAPC varies with culture conditions and that this may be an important consideration where BMAPC are to be used in vivo in immunotherapeutic regimens.

Animals↗
PubMed1995

Dendritic cell presentation of PPD and 19 kDa protein of Mycobacterium tuberculosis and emergent T helper cell phenotype.

Protection against infection with Mycobacterium tuberculosis is preferentially associated with the development of the T helper 1 subset, IFN-gamma production and a cell-mediated response, rather than with T helper 2 cells, 4 (IL-4) and antibody production. The type of APC interacting with T cells responsive to mycobacterial peptides may influence which of these responses predominates. This investigation focuses on the role of dendritic cells (DC) because they are the most potent APC in both primary and recall immune responses. Our results show that splenic DC-enriched suspensions prepared from C57BL/6 mice and pulsed with either purified protein derivative (PPD) or the immunodominant 19 kDa protein from M. tuberculosis, can activate antigen-primed T cells in vitro, whereas spleen cell suspensions depleted of DC cannot. DC pulsed with PPD or 19 kDa antigen are able to prime naive T cells in vivo. Supernatants collected from cultures containing T cells from mice injected with PPD-pulsed DC and then challenged in vitro with PPD-pulsed DC were found to contain more IL-2 and IFN-gamma than those from control mice which received either DC or PPD alone. No such antigen-specific IFN-gamma response occurred if DC pulsed with 19 kDa were used in place of PPD-pulsed DC. IL-4 was not detected in any of the culture supernatants. We conclude that DC can induce production of cytokines associated with a protective immune response when presenting peptides derived from heterogeneous mycobacterial antigens but not when exposed to the single 19 kDa immunodominant protein.

Animals↗
PubMed1995

Prevention in college health: counseling perspectives.

Such problems as sexually transmitted diseases, alcohol and other drug use, and acquaintance rape require college health professionals to function in primary and secondary preventive roles. In this article, the authors draw upon counseling literature and college health practice to identify the central elements of preventive programs, highlight specific intervention formats used in preventive work, and describe how interventions are assembled into coherent programs of prevention. To illustrate the structure and process of long-range, institutionalized preventive efforts, the authors describe an initiative addressing the primary, secondary, and tertiary prevention of substance use at a health sciences campus.

Adult↗
PubMed1995

Antigen-pulsed, interleukin-4-treated B cells activate primed T cells in vitro but not naive T cells in vivo.

The ability of B cells to act as effective antigen-presenting cells is a source of debate which centres on the degree of activation of either B cells or T cells. We have investigated whether B cells treated with interleukin 4 (IL-4) can express the two signals required to activate T cells: MHC Class 2/antigenic peptide complexes(signal 1) and the costimulatory molecules B7-1 and B7-2 (signal 2). We have also determined whether these cells could activate antigen-experienced T cells in vitro and whether they could prime naive T cells in vivo. We found that B cells expressed abundant MHC Class 2 molecules and moderate levels of B7-2 after 24 h culture in IL-4 with or without purified protein derivative (PPD) but B7-1 was not detectable. PPD-pulsed, IL-4 treated B cells induced antigen-experienced T cells to proliferate in vitro but these cells failed to prime naive T cells in vivo when injected into mice. We conclude that signals, in addition to those induced with IL-4, are required for B cells to initiate an immune response to antigen.

Animals↗
PubMed1994

Levels of physician involvement with patients and their families. A model for teaching and research.

BACKGROUND: We present an educational model that describes physician skills for addressing psychosocial concerns of patients, ranging from basic medical questions to in-depth psychotherapy. This model improves upon previously published models by integrating into one hierarchy levels of physician involvement with individual patients and levels of involvement with families. METHODS: Ten faculty family physicians were videotaped during 200 office visits. Interviews were categorized according to the model, with a 79% interrater agreement. RESULTS: Most visits involved the lower three levels of physician involvement (41%, level 1; 35.5%, level 2; and 23%, level 3). Discussion of family context occurred in a majority (58.5%) of visits, primarily when another family member was in the room and during preventive care visits. Higher levels were associated with longer visits--about 3 minutes more for each additional level. CONCLUSIONS: This investigation suggests that the levels of physician involvement model can be reliably measured. This model may be a useful tool for education and research, particularly the study of physician interview skills appropriate to family medicine.

Adult↗
PubMed1993

Levels of physician involvement with psychosocial concerns of individual patients: a developmental model.

BACKGROUND: Physician involvement in patients' psychosocial concerns is seen as desirable by practicing physicians and family medicine educators. Although the effectiveness of several approaches to psychosocial problems has been demonstrated, the skills required of the physician vary widely. We present a five-level developmental model of physician skills in addressing the psychosocial concerns of individual patients. METHODS: To validate the model, 171 outpatient office visits in a residency program were videotaped and rated according to the levels. The inter-rater agreement was 88%. RESULTS: Interviews with lower levels of psychosocial involvement occurred much more frequently than interviews rated at higher levels (48%, 34%, 16%, 2%, 0%, respectively). Involvement at each higher level added approximately two minutes to the length of the visit. The development of higher levels of physician involvement between the first and third year of residency training was not found in this sample. CONCLUSIONS: These results support the validity of the five-level sequence regarding the depth of physician involvement. Because the hierarchy can be used to reliably assess the degree of physician involvement with the psychosocial concerns of individual patients, the model offers potential applications for resident education and further research on the physician-patient relationship.

Clinical Competence↗
PubMed1992

Evidence that changes in expression of major histocompatibility complex antigens may underlie the immunosuppressive effect of heat-treated cells in vivo and in vitro.

The prior transfusion of heat-treated (60 degrees C for 1 hr) allogeneic spleen cells is known to bring about specific prolongation of the survival of subsequent donor strain heart allografts. In this communication we show that some polymorphic and monomorphic class 1 determinants on spleen cells are heat denatured so that they no longer provoke antibody formation in naive allogeneic hosts. By contrast, the heated cells remain able to provoke the formation of anti-class 2 antibodies. When measured in a binding assay, the levels of anti-class 2 antibodies are similar irrespective of whether the immunizing inoculum consists of normal or heated cells. In a cytotoxic assay, the antibodies produced following exposure to normal cells are cytotoxic; this activity is substantially reduced when the cellular immunizing inoculum is heated. Cells heated to 60 degrees C for 1 hr are unable to stimulate in a mixed lymphocyte reaction, but reactivity can be partially restored by the addition of exogenous IL-2 to the culture. From previous evidence it seems unlikely that suppressor cells play a major role in the immunosuppression effected by cells heated to 60 degrees C. The results presented in this communication suggest a possible role for anticlass 2 antibodies and also imply the defective production of a costimulatory signal that normally follows the presentation of allogeneic MHC antigens.

Animals↗